Vitamin D analogues

ABSTRACT

The present invention relates to compounds of formula (I) ##STR1## in which R 1  and R 2  may be the same or different and stand for hydrogen, lower alkyl, lower cycloalkyl, or, taken together with the carbon atom (starred in formula I), bearing the groups X, R 1  and R 2 , can form a C 3  -C 8  carbocyclic ring; X stands for hydrogen or hydroxy, R 3  and R 4 , which may be the same or different stand for hydrogen, lower alkyl or halogen, n is 0, 1 or 2 and m is 0, 1 or 2. The present compounds, which find use both in the human and veterinary practice, show an immunomodulating effect as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells.

This invention relates to a hitherto unknown class of compounds whichshows an immunomodulating effect as well as strong activity in inducingdifferentiation and inhibiting undesirable proliferation of certaincells, including cancer cells and skin cells, to pharmaceuticalpreparations containing these compounds, to dosage units of suchpreparations, and to their use in the treatment and prophylaxis ofautoimmune diseases, including diabetes mellitus, hypertension,inflammatory diseases such as rheumatoid arthritis and asthma as well asdiseases characterized by abnormal cell differentiation and/or cellproliferation, and/or imbalance in the immune system.

The compounds of the present invention are represented by the generalformula I ##STR2## in which R¹ and R² may be the same or different andstand for hydrogen, lower alkyl, lower cycloalkyl, or, taken togetherwith the carbon atom (starred in formula I), bearing the groups X, R¹and R² can form a C₃ -C₈ carbocyclic ring; X stands for hydrogen orhydroxy, R³ and R⁴, which may be the same or different stand forhydrogen, lower alkyl or halogen, n is 0, 1 or 2 and m is 0, 1 or 2.

In the context of this invention, the expression "lower alkyl" indicatesa straight or branched saturated or unsaturated carbon chain containingfrom 1 to 5 carbon atoms, and the expression "lower cyclo-alkyl"indicates a saturated or unsaturated C₃ -C₇ carbocyclic ring.

As can be seen from formula I, depending on the meanings of X, R¹ and R²the compounds of the invention can comprise several diastereoisomericforms (e.g. R or S configuration at the starred carbon atom). Theinvention covers all these diastereoisomers in pure form and alsomixtures of diastereoisomers. In addition, derivatives of I in which oneor more of the hydroxy groups are masked as groups which can bereconverted to hydroxy groups in vivo are also within the scope of theinvention ("bioreversible derivatives or prodrugs of I").

The term "bioreversible derivatives or prodrugs of I" includes, but isnot limited to, derivatives of the compounds of formula I in which oneor more hydroxy groups have been transformed into --O--acyl or--O--glycosyl groups, or a phosphate ester, such masked groups beinghydrolyzable in vivo.

Compounds of formula I in which X is hydrogen are another type ofprodrug. These compounds are relatively inactive in vitro, but areconverted to active compounds of formula I (X =OH) by enzymatichydroxylation after administration to the patient.

It has recently been shown that 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂ D₃)influences the effects and/or production of interleukins, indicating thepotential use of this compound in the treatment of diseasescharacterized by a dysfunction of the immune system, e.g. autoimmunediseases and rejection of transplants. In addition, other conditionscharacterized by an abnormal interleukin-1 production, e.g. inflammatorydiseases such as rheumatoid arthritis may be treated with 1,25(OH)₂ D₃.

It has also been shown that 1,25(OH)₂ D₃ is able to stimulate thedifferentiation of cells and inhibit excessive cell proliferation, andit has been suggested that this compound might be useful in thetreatment of diseases characterized by abnormal cell proliferationand/or cell differentiation such as cancer and psoriasis.

Also, the use of 1,25(OH)₂ D₃ for the treatment of hypertension anddiabetes mellitus has been suggested.

However, the therapeutic possibilities in such indications of 1,25(OH)₂D₃ are severely limited by the well known potent effect of this hormoneon calcium metabolism; elevated blood concentrations will rapidly giverise to hypercalcemia. Thus, this compound and its potent syntheticanalogues are not completely satisfatory for use as drugs in thetreatment of e.g. psoriasis, cancer or immune diseases which may requirecontinuous administration of the drug in relatively high doses.

A number of oxa-analogues of vitamin D₃ are known.1α,25-dihydroxy-20-oxa-21-norvitamin D₃ and1α-hydroxy-20-oxa-21-norvitamin D₃ are described in N. Kubodera et al,Chem. Pharm. Bull., 34, 2286 (1986), 1α,25-dihydroxy-22-oxavitamin D₃and 25-hydroxy-22-oxavitamin D₃ are described in E. Murayama et al,Chem. Pharm. Bull., 34, 4410 (1986), J. Abe et al, FEBS LETTER, 226, 58(1987) and European Patent Application, publication number 184 112,1α,25-dihydroxy-23-oxavitamin D₃ is described in European PatentApplication, publication number 78704, and a number of 22-oxa-analoguesof vitamin D₃ are described in International Patent Applications NosPCT/DK90/00037 and PCT/DK90/00036, both filed on Feb. 13, 1990.

In vitro experiments indicate that some of these compounds may haveadvantages over 1,25(OH)₂ D₃. Thus 1α,25-dihydroxy-22-oxavitamin D₃ hasonly one 14th as much affinity as 1α,25(OH)₂ D₃ for the chick intestinalcytosolic receptor, a weaker affinity than 1,25(OH)₂ D₃ for the receptorin a human myeloid leukemia cell line (HL-60), and a high activity asinducer of differentiation in HL-60 cells.

In contrast to the compounds of the present invention the abovementioned 22-oxa-compounds do not contain an aromatic ring.

The usefulness of a vitamin D analogue in the above mentionedindications is dependent not only upon a favourable ratio of bindingaffinity to relevant receptors compared to the intestinal receptor, butalso upon the fate of the compound in the organism.

It has now been found that the compounds of the present invention showfavourable selectivity with respect to receptor binding and at the sametime show high bioavailability as well as chemical and metabolicstability.

The selectivity of the compounds is illustrated by the fact that whilethey have high affinities for the receptor in tumour cells (similar toor much better than that of 1,25(OH)₂ D₃) and the concentration neededto induce cell differentiation in a human monocytic tumour cell line isthe same as or considerably lower than that needed of 1,25(OH)₂ D₃ togive the same effect, their binding affinity for the intestinal receptoris lower than that of 1,25(OH)₂ D₃. In vivo in rats the compounds areless active than 1,25(OH)₂ D₃ in inducing hypercalciuria andhypercalcemia.

This renders the compounds of the invention especially suited for bothlocal and systemic treatment and prophylaxis of human and veterinarydisorders which are characterized by abnormal cell proliferation and/orcell differentiation, such as certain dermatological disorders includingpsoriasis and acne, and certain cancer forms, e.g. leukemia andmyelofibrosis, and diseases characterized by an imbalance in the immunesystem, e.g autoimmune diseases or AIDS, and to obtain desiredimmunosuppression as in transplantation procedures, as well as treatmentof diabetes mellitus and hypertension and inflammatory diseases, such asrheumatoid arthritis and asthma. As the compounds of this invention maypromote the differentiation of the hair follicle cells, these compoundsmay be used in the treatment of alopecia. Preliminary studies indicatethat the compounds of the invention may reverse the unattractiveconcomitants of skin ageing, e.g. on photoaged skin.

The compounds of formula I may conveniently be prepared from the vitaminD-derivative 1 (or its 20R isomer) (Tetrahedron, 43, 4609 (1987)) by theroutes outlined in Scheme 1. Oxidation of 1 for example using the vanRheenen procedure (Tetrahedron Letters, 1969, 985) gives the ketone 2,which is reduced to the 20R-alcohol 3. When a suitable chiral reducingagent is used 3 may be prepared with very high stereoselectivity, but 3is conveniently prepared by NaBH₄ reduction of 2 and separating theminor amount of corresponding 20S-alcohol chromatographically.O-Alkylation of 3 to give III is achieved by treatment under basicconditions with a side chain building block of general formula Z-R, inwhich Z is a leaving group such as a halogen (Cl, Br or I) orp-toluenesulphonyloxy or methanesulphonyloxy, and R is as defined in thenotes to Scheme 1. Thus R in compounds III, IV, V and VI does notnecessarily have the same meaning along a particular synthetic sequence,and the conversion of R to the side chain in I may well involve severalsteps. Apart from any necessary modification within the side chain (R),the conversion of III to I involves a photoisomerisation step and adesilylation step, analogous to the steps used in the last stages of thesynthesis of other vitamin D analogues (see European patent No. 0 227826).

The side chain building blocks, RZ, are either known compounds or may beprepared analogously to those described in PCT/DK89/00079. They maytypically be prepared by the routes outlined in Scheme 2.

The following standard abbreviations are used throughout thisdisclosure: Me=methyl; Et=ethyl; Pr^(n) =n-propyl; Pr^(i) =isopropyl;Bu^(t) =tert-butyl; THP=tetra-hydro-4H-pyran-2-yl; THF=tetrahydrofuran:Ts=p-toluenesulphonyl; TBA=tetra-(n-butyl)-ammonium. ##STR3## where Y ishydrogen or hydroxyl in which the hydroxyl group may optionally beprotected by a protective groups, such as trialkylsilyl or THP. n, m,R¹, R², R³, and R⁴ are as defined as above.

a) Oxidation e.g. with O₂ with Cu(AcO)₂, 2,2'-bipyridyl and1,4-diazabicyclo[2,2,2]octane as catalyst.

b) Reduction (e.g. with NaBH₄).

c) Alkylation with the side chain fragment R-Z in the presence of base(e.g. KOH, KOBu^(t) or KH, with or without catalyst (e.g. 18-Crown-6) insolvent, e.g. THF.

d) Optional functional group modification in the side chain.

e) Isomerisation with hν - triplet sensitizer, e.g. anthracene.

f) Deprotection with TBA⁺ F⁻ or HF.

It should be noted that although the shown intermediates may havehydroxyl groups protected as tert-butyldimethylsilyl ethers, the scopeof the invention does not exclude the use of alternative hydroxylprotecting groups well known in the art (such as those described in T.W. Greene, "Protective groups in organic synthesis", Wiley, New York,1981), together with alternative reactions for deprotection. ##STR4##

The present compounds are intended for use in pharmaceuticalcompositions which are useful in the treatment of human and veterinarydisorders as described above.

The amount required of a compound of formula I (hereinafter referred toas the active ingredient) for therapeutic effect will, of course, varyboth with the particular compound, the route of administration and themammal under treatment. The compounds of the invention can beadministered by the parenteral, intra-articular, enteral or topicalroutes. They are well absorbed when given enterally and this is thepreferred route of administration in the treatment of systemicdisorders. In the treatment of dermatological disorders like psoriasis,topical or enteral forms are preferred.

In the treatment of respiratory diseases like asthma an aerosol ispreferred.

While it is possible for an active ingredient to be administered aloneas the raw chemical, it is preferable to present it as a pharmaceuticalformulation. Conveniently, the active ingredient comprises from 1 ppm to0.1% by weight of the formulation.

By the term "dosage unit" is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically and chemically stable unitdose comprising either the active material as such or a mixture of itwith solid or liquid pharmaceutical diluents or carriers.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier therefore and optionally othertherapeutic ingredient(s). The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the formulationsand not deleterious to the recipient thereof.

The formulations include e.g. those in a form suitable for oral, rectal,parenteral (including subcutaneous, intramuscular and intravenous),intra-articular and topical administration.

The formulations may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be administered in the form of a bolus,electuary or paste.

A tablet may be made by compressing or moulding the active ingredientoptionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed by a binder, lubricant, inert diluent, surface activeor dispersing agent. Moulded tablets may be made by moulding, in asuitable machine, a mixture of the powdered active ingredient andsuitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the active ingredientwhich is preferably isotonic with the blood of the recipient.

Formulations suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the active ingredient which maybe in microcrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems may also be used to present the active ingredient forboth intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyeformulations, include liquid or semi-liquid preparations such asliniments, lotions, applicants, oil-in-water or water-in-oil emulsionssuch as creams, ointments, including eye ointments, pastes; or solutionsor suspensions such as drops, including eye-drops.

For asthma treatment inhalation of powder, self-propelling or sprayformulations, dispensed with a spray can, a nebulizer or an atomizer canbe used. The formulations, when dispensed, preferably have a particlesize in the range of 10 to 100μ.

Such formulations are most preferably in the form of a finely comminutedpowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect may beachieved either by choice of a valve having the desired spraycharacteristics (i.e. being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. These self-propellingformulations may be either powder-dispensing formulations orformulations dispensing the active ingredient as droplets of a solutionor suspension.

Self-propelling powder-dispensing formulations preferably comprisedispersed particles of solid active ingredients, and a liquid propellanthaving a boiling point below 18° C. at atmospheric pressure. The liquidpropellant may be any propellant known to be suitable for medicinaladministration and may comprise one or more C₁ -C₆ -alkyl hydrocarbonsor halogenated C₁ -C₆ -alkyl hydrocarbons or mixtures thereof;chlorinated and flourinated C₁ -C₆ -alkyl hydrocarbons are especiallypreferred. Generally, the propellant constitutes 45 to 99.9% w/w of theformulation whilst the active ingredient constitutes 1 ppm to 0.1% w/w,of the formulation.

In addition to the aforementioned ingredients, the formulations of thisinvention may include one or more additional ingredients such asdiluents, buffers, flavouring agents, binders, surface active agents,thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate(including anti-oxidants), emulsifying agents and the like.

The compositions may further contain other therapeutically activecompounds usually applied in the treatment of the above mentionedpathological conditions.

The present invention further concerns a method for treating patientssuffering from one of the above pathological conditions, said methodconsisting of administering to a patient in need of treatment aneffective amount of one or more compounds of formula I, alone or incombination with one or more other therapeutically active compoundsusually applied in the treatment of said pathological conditions. Thetreatment with the present compounds and/or with further therapeuticallyactive compounds may be simultaneous or with intervals.

In the treatment of systemic disorders daily doses of from 0.1-100 μg,preferably from 0.2-25 μg, of a compound of formula I are administered.In the topical treatment of dermatological disorders, ointments, creamsor lotions containing from 1-1000 μg/g, and preferably from 10-500 μg/g,of a compound of formula I are administered. The oral compositions areformulated, preferably as tablets, capsules, or drops, containing from0.1-50 μg, preferably from 0.2-25 μg, of a compound of formula I, perdosage unit.

The invention will now be further described in the followingnon-limiting Preparations and Examples:

PREPARATIONS AND EXAMPLES General

The exemplified compounds I are listed in Table 1. The intermediates ofScheme I referred to in the Preparations are to be identified by numberswith the corresponding formulae in Table 2.

For nuclear magnetic resonance spectra (300 MHz) chemical shift values(δ) are quoted for deuteriochloroform solutions relative to internaltetramethylsilane (δ=0) or chloroform (δ=7.25). The value for amultiplet, either defined (doublet (d), triplet (t), quartet (q)) or not(m) at the approximate mid point is given unless a range is quoted(s=singlet, b=broad). Coupling constants (J) are given in Hertz, and aresometimes approximated to the nearest unit.

Ether is diethyl ether, and was dried over sodium. THF was dried oversodium-benzophenone. Petroleum ether refers to the pentane fraction.Reactions were run at room temperature unless otherwise noted. Thework-up procedure referred to involves dilution with the specifiedsolvent (otherwise the organic reaction solvent), extraction with waterand then brine, drying over anhydrous MgSO₄, and concentration in vacuoto give a residue.

                                      TABLE 1                                     __________________________________________________________________________    Exemplified Compounds I                                                        Compound No.                                                                          Example No.                                                                          n                                                                               m                                                                               R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                          R.sup.4                                                                         X                                                                                ##STR5##                                    __________________________________________________________________________    101     1      1 0 Me Me H  H OH 3                                            102     2      1 0 Me Me H  H OH 4                                            103     3      1 0 Et Et H  H OH 3                                            104     4      1 1 Me Me H  H OH 2                                            105     5      1 0 Me Me 6-Me                                                                             H OH 3                                            106     6      2 0 Pr.sup.n                                                                         Pr.sup.n                                                                         H  H OH 2                                            107     7      1 0 Me Me 2-F                                                                              H OH 4                                            __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     Preparations of formula III or IV                                            (See Scheme 1)                                                                 Compound No.                                                                          Preparation No.                                                                       Type (Scheme 1)                                                                        n                                                                               m                                                                               R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                          R.sup.4                                                                         Y                                                                                 ##STR6##                         __________________________________________________________________________     4       4      III      1 0 Me Me H  H O-THP                                                                             3                                  5       5      IV       1 0 Me Me H  H O-THP                                                                             3                                  6       7      III      1 0 Me Me H  H O-THP                                                                             4                                  7       8      IV       1 0 Me Me H  H O-THP                                                                             4                                  8      10      III      1 0 Et Et H  H O-THP                                                                             3                                  9      11      IV       1 0 Et Et H  H O-THP                                                                             3                                 10      13      III      1 1 Me Me H  H O-THP                                                                             2                                 11      14      IV       1 1 Me Me H  H O-THP                                                                             2                                 12      16      III      1 0 Me Me 6-Me                                                                             H O-THP                                                                             3                                 13      17      IV       1 0 Me Me 6-Me                                                                             H O-THP                                                                             3                                 14      19      III      2 0 Pr.sup.n                                                                         Pr.sup.n                                                                         H  H O-THP                                                                             2                                 15      20      IV       2 0 Pr.sup.n                                                                         Pr.sup.n                                                                         H  H O-THP                                                                             2                                 16      23      III      1 0 Me Me 2-F                                                                              H O-THP                                                                             4                                 17      24      IV       1 0 Me Me 2-F                                                                              H O-THP                                                                             4                                 __________________________________________________________________________

Preparation 1: Compound 2

To a solution of1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5(E),(7E),10(19)-triene(3.44 g, 6 mmol) in N,N-dimethylformamide (150 ml),1,4-diazabicyclo[2.2.2]octane (600 mg, 5.3 mmol), cupric acetate,monohydrate (90 mg, 0.45 mmol) and 2,2'-bipyridyl (72 mg, 0.45 mmol)were added. Air was bubbled through the well stirred solution for 6 daysat 40° C.

The reaction mixture was diluted with ethyl acetate (500 ml), extractedwith water (2×100 ml) and saturated aqueous sodium chloride (3×50 ml)and dried over MgSO₄. Ethyl acetate was evaporated off, and the solidresidue was purified by chromatography (silica gel, 10% ether inpetroleum ether as eluant) to give the title compound.

NMR: δ=0.037 (s, 3H), 0.043 (s, 3H), 0.056 (s, 6H), 0.49 (s, 3H), 0.84(s, 9H), 0.89 (s, 9H), 1.5-2.30 (m, 13H), 2.13 (s, 3H), 2.55 (dd, 1H),2.70 (t, 1H), 2.89 (bd, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (m, 1H),4.98 (m, 1H), 5.83 (d, 1H), 6.43 (d, 1H) ppm.

Preparation 2: Compound 3 and its 20S-isomer

Compound 2 (Prep. 1) (3.10 g, 5.5 mmol) was dissolved in tetrahydrofuran(140 ml) and sodium borohydride (0.35 g, 3.3 mmol) was added. Methanol(100 ml) was then added dropwise over 15 minutes. The reaction blend wasstirred for 20 minutes, then diluted with ethyl acetate (560 ml). Thesolution was extracted with water (5×150 ml) and saturated aqueoussodium chloride (150 ml), dried over MgSO₄ and evaporated to give acolourless oil. The oily residue was purified by chromatography (silicagel, 15% ethyl acetate in petroleum ether as eluant). The first elutedisomer (3A) was dissolved in methanol (3 ml). Upon scratching acrystalline product precipitated. The suspension was stirred for 1 h atroom temperature and 1 h in an ice bath. The crystals were collected ona filter and dried in a desiccator over the week-end.

Mp. 131°-146° C.

NMR: δ=0.05 (m, 12H), 0.62 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H),1.10-2.10 (m, 14H), 1.15 (d, 3H), 2.30 (bd, 1H), 2.53 (dd, 1H), 2.89 (m,1H), 2.89 (m, 1H), 3.71 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m,1H), 4.98 (m, 1H), 5.81 (d, 1H), 6.45 (d, 1H) ppm.

The fractions containing the more polar 20S-isomer were evaporated togive a colourless residue.

NMR: δ=0.052 (bd, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.22(d, 3H), 1.20-2.10 (m, 14H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.87 (m, 1H),3.72 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (bs, 1H), 4.98 (m, 1H),5.82 (d, 1H ), 6.44 ( d, 1H ) ppm.

A sample of the residue was dissolved in methanol. Upon scratching acrystalline product was formed. The suspension was placed in therefrigerator over the week-end. The crystals were collected on a filterand dried in a desiccator.

M.p. 58°-63° C.

Preparation 3:2-[2-(3-Bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran

To a stirred, ice-cooled solution of methyl 3-bromo-methyl-benzoate(6.12 g, 27 mmol) in dried ether (20 ml) was added dropwise over 30minutes a filtered solution of a Grignard reagent, prepared frommagnesium (1.47 g, 60 mmol) and methyl iodide (4.0 ml, 64 mmol) in driedether (40 ml). After a further 20 minutes in the ice-bath, water (40 ml)was slowly poured onto the reaction mixture. The phases were separated,and the aqueous phase was extracted with ether (3×50 ml). The combinedether phases were consecutively extracted with water (3×50 ml) andsaturated aqueous sodium chloride (50 ml), dried with MgSO₄ andconcentrated in vacuo to yield a dark oil.

The crude oil was then purified by chromatography (silica gel, 25% etherin petroleum ether as eluant) to yield the intermediate2-(3-bromomethylphenyl)-propan-2-ol as a yellow oil.

The intermediate was dissolved in methylene chloride (100 ml),3,4-dihydro-2H-pyran (2.4 ml, 26 mmol) and pyridinium p-toluenesulfonate (0.43 g, 1.7 mmol) were added, and the mixture was stirred atroom temperature for 4 hours. The reaction mixture was diluted withether (150 ml) and extracted with water (3×50 ml) and saturated aqueoussodium chloride (50 ml), dried and concentrated in vacuo. The productwas then purified by chromatography (silica gel, 10% ether in petroleumether as eluant) to give a colourless oil.

NMR: δ=1.52 (s, 3H), 1.67 (s, 3H), 1.35-1.75 (m, 5H), 1.85 (m, 1H), 3.39(m, 1H), 3.95 (m, 1H), 4.43 (dd, 1H), 4.51 (AB quartet, 2H), 7.28 (m,2H), 7.38 (m, 1H), 7.49 (m, 1H) ppm.

Preparation 4: Compound 4(R=3-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-phenyl-methyl)

To a solution of compound 3 (841 mg, 1.5 mmol) in dry tetrahydrofuran(10 ml), potassium hydride (1.0 ml, 20% suspension in oil) and2-[2-(3-bromomethylphenyl)-2-propyl]tetrahydro-4H-pyran (2.01 ml), 6.75mmol) were added, and the reaction mixture stirred vigorously.18-Crown-6 (650 mg, 5.8 mmol) was dissolved in dry tetrahydrofuran (5ml) and added dropwise over 20 minutes. After a further 90 minutesstirring, water (40 ml) was carefully added to the reaction mixture.After the reaction had subsided, the reaction mixture was diluted withether (100 ml), and the organic phase consecutively extracted with water(3×50 ml) and aqueous saturated sodium chloride (50 ml). After dryingand the removal of the solvent in vacuo, the product was purified bychromatography (silica gel, 10% ether in petroleum ether as eluant) togive the desired compound as a colourless oil.

NMR: δ=0.06 (bs, 12H), 0.52 and 0.54 (2s, 3H), 0.85 (s, 9H), 0.89 (s,9H), 1.17 (d, 3H), 1.49 (bs, 3H), 1.65 (bs, 3H), 1.10-1.98 (m, 17H),2.04 (m, 1H), 2.22(m, 1H), 2.31 (bd, 1H), 2.54 (dd, 1H), 2.86 (bd, 1H),3.37 (m, 1H), 3.45 (m, 1H), 3.94 (m, 1H), 4.21 (m, 1H), 4.34 (d, J=11.3,1H), 4.39 (m, 1H), 4.53 (m, 1H), 4.60 (d, J=11.3, 1H), 4.93 (m, 1H),4.98 (m, 1H), 5.80 (d, J=11.4, 1H), 6.45 (d, J=11.4, 1H), 7.20 (bd, 1H),7.28 (t, 1H), 7,36 (bd, 1H), 7.44 (bs, 1H) ppm.

Preparation 5: Compound 5(R=3-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-phenyl-methyl)

A solution of compound 4 (Prep. 4) (800 mg, 1.0 mmol ), anthracene (800mg, 4.5 mmol) and triethylamine (1 drop) in dichloromethane (60 ml )under nitrogen in a Pyrex flask was irradiated with light from a highpressure ultra-violet lamp, type TQ 718-Z2 (Hanau), at room temperaturefor 35 minutes. The solution was filtered and concentrated in vacuo. Theresidue was purified by chromatography (silica gel, 10% ether inpetroleum ether as eluant) to give the desired compound as a colourlessoil.

NMR: δ=0.05 (bs, 12H), 0.50 and 0.53 (2s, 3H), 0.87 (s, 18H), 1.16 (d,3H), 1.48 (bs, 3H), 1.65 (bs, 3H), 1.10-1.93 (m, 17H), 2.00 (t, 1H),2.20 (m, 2H), 2.44 (m, 1H), 2.81 (bd, 1H), 3.38 (m, 1H), 3.45 (m, 1H),3.95 (m, 1H), 4.18 (m, 1H), 4.34 (d, J=11.4, 1H), 4.40 (m, 2H), 4.59 (d,J=11.4, 1H), 4.85 (m, 1H), 5.16 (m, 1H), 5.99 (d, J=11.1, 1H), 6.23 (d,J=11.1, 1H), 7.19 (bd, 1H), 7.28 (t, 1H), 7,36 (bd, 1H), 7.44 (bd, 1 H)ppm.

Preparation 6:2-[2-(4-Bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran

By following the procedure of Preparation 3 and substituting methyl4-bromomethyl-benzoate for methyl 3-bromomethyl-benzoate, the titlecompounds was prepared.

NMR: δ=1.50 (s, 3H), 1.66 (s, 3H), 1.35-1.70 (m, 5H), 1.85 (m, 1H), 3.40(m, 1H), 3.95 (m, 1H), 4.44 (m, 1H), 4.50 (s, 2H), 7.37 (m, 4H).

Preparation 7: Compound 6 (R=4-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-phenyl-methyl)

This compound was prepared by following the procedure of Preparation 4and substituting 2-[2-(4-bromomethylphenyl)-2-propyl]-tetrahydro-4H-pyran for 2-[2-(3-bromomethylphenyl)-2-propyl]-tetrahydro-4H-pyran.

NMR: δ=0.06 (bs, 12H), 0.52 and 0.53 (2s, 3H), 0.86 (s, 9H), 0.89 (s,9H), 1.17 (d, 3H), 1.49 (bs, 3H), 1.66 (bs, 3H), 1.10-1.97 (m, 17H),2.05 (m, 1H), 2.16 (m, 1H), 2.31 (bd, 1H), 2.54 (dd, 1H), 2.87 (bd, 1H),3.37 (m, 1H), 3.45 (m, 1H), 3.95 (m, 1H), 4.21 (m, 1H), 4.36 (d, J=11.2,1H), 4.40 (m, 1H), 4.52 (m, 1H), 4.57 d, J=11.2, 1H), 4.93 (m, 1H), 4.98(m, 1H), 5.80 (d, J=11.4, 1H), 6.46 (d, J=11.4, 1H), 7.30 (d, 2 H), 7.40(bs, 2H) ppm.

Preparation 8: Compound 7(R=3-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-phenyl-methyl)

This compound was prepared by following the procedure of Preparation 5and substituting compound 5 (Prep. 7) for compound 5 (Prep. 4).

NMR: δ=0.06 (bs, 12H), 0.50 and 0.52 (2s, 3H), 0.87 (bs, 18H), 1.16 (d,3H), 1.49 (bs, 3H), 1.66 (bs, 3H), 1.00-1.92 (m, 17H), 2.00 (bt, 1H),2.20 (m, 2H), 2,45 (dd, 1H), 2.82 (bd, 1H), 3.40 (m, 2H), 3.95 (m, 1H),4.18 (m, 1H), 4.37 (m, 1H), 4.56 (d, J=11.3, 1H), 4.86 (m, 1H), 5.17 (m,1H), 5.99 (d, J=11.0, 1H), 6.23 (d, J=11.0, 1H), 7.30 (d, 2H), 7.41 (d,2H) ppm.

Preparation 9:2-[3-(3-Bromomethylphenyl)-3-pentyl-oxy]-tetrahydro-4H-pyran

The compound was prepared according to the procedure described inPreparation 3, except that methyl magnesium iodide was substituted withethyl magnesium bromide.

NMR: δ=0.63 (t, 3H), 0.77 (t, 3H), 1.42-1.75 (m, 5H), 1.77-2.15 (m, 5H),3.43 (m, 1H), 4.00 (m, 1H), 4.52 (AB q, 2H), 4.58 (m, 1H), 7.20-7.38 (m,3H), 7.45 (bs, 1H) ppm.

Preparation 10: Compound 8 (R=3-[3-(tetrahydro-4H-pyran-2-yl)-oxy-pentyl-3]-phenyl-methyl)

The compound was prepared according to the procedure described inPreparation 4, except that 2-[2-(3-bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran was substituted with2-[3-(3-bromomethylphenyl)-3-pentyl-oxy]-tetrahydro-4H-pyran.

NMR: δ=0.06 (m, 12H), 0.53 (s, 0.5×3H), 0.54 (s, 0.5×3H), 0.59 (t, 3H),0.76 (dt, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.17 (d, 3H), 1.10-2.12 (m,22H), 2.19 (bd, 1H), 2.30 (bd, 1H), 2.54 (dd, 1H), 2.85 (bd, 1H), 3.44(m, 2H), 3.97 (m, 1H), 4.21 (m, 1H),. 4.33 (d, 1H), 4.57 (m, 3H), 4.93(m, 1H), 4.98 (m, 1H), 5.80 (d, 1H), 6.45 (d, 1H), 7.10-7.45 (m, 4H)ppm.

Preparation 11: Compound 9(R=3-[3-(tetrahydro-4H-pyran-2-yl)-oxy-pentyl-3]-phenyl-methyl)

The compound was prepared according to the procedure described inPreparation 5, except that the compound 4 prepared in Preparation 4 wassubstituted with the compound 8 prepared in Preparation 10.

NMR: δ=0.05 (m, 12H), 0.51 (s, 0.5×3H), 0.52 (s, 0.5×3H), 0.59 (t, 3H),0.76 (dt, 3H), 0.87 (s, 18H), 1.16 (d, 3H), 1.05-2.10 (m, 22H), 2.20 (m,2H), 2.44 (dd, 1H), 2.80 (bd, 1H), 3.43 (m, 2H), 3.97 (m, 1H), 4.18 (m,1H), 4.32 (d, 1H), 4.36 (m, 1H), 4.56 (m, 2H), 4.85 (m, 1H), 5.17 (m,1H), 5.98 (d, 1H), 6.23 (d, 1H), 7.18 (d, 1H), 7.27 (t, 1H), 7.34 (d,1H), 7.39 (bd, 1H) ppm.

Preparation 12:2-[1-(2-Chloromethylphenyl)-2-methyl-2-propyl-oxy]-tetrahydro-4 H-pyran

The compound is prepared according to the procedure described inPreparation 3, except that methyl 3-bromomethyl-benzoate is substitutedwith methyl 2-chloromethylphenylacetate.

Preparation 13: Compound 10(R=2-[2-(tetrahydro-4H-pyran-2-yl)-oxy-2-methyl-propyl]-phenylmethyl)

The compound is prepared according to the procedure described inPreparation 4, except that2-[2-(3-bromomethyl-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran issubstituted with2-[2-(2-chloromethylphenyl)-2-methyl-2-propyl-oxy]-tetrahydro-4H-pyran.

Preparation 14: Compound 11(R=2-[2-(tetrahydro-4H-pyran-2-yl)-oxy-2-methyl-propyl]-phenylmethyl)

The compound is prepared according to the procedure described inPreparation 5, except that the compound 4 prepared in Preparation 4 issubstituted with the compound 10 prepared in Preparation 13.

Preparation 15:2-[2-(3-Chloromethyl-4-methyl-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran

The compound is prepared according to the procedure described inPreparation 3, except that methyl 3-bromomethyl-benzoate is substitutedwith methyl 3-chloromethyl-4-methyl-benzoate.

Preparation 16: Compound 12(R=3-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-6-methyl-phenylmethyl)

The compound is prepared according to the procedure described inPreparation 4, except that2-[2-(3-bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran issubstituted with2-[2-(3-chloromethyl-4-methyl-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran.

Preparation 17: Compound 13(R=3-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-6-methylphenylmethyl)

The compound is prepared according to the procedure described inPreparation 5, except that the compound 4 prepared in Preparation 4 issubstituted with the compound 12 prepared in Preparation 16.

Preparation 18: 2-[4-(2-(2-bromoethyl)-phenyl)-4-heptyl-oxy]-tetrahydro-4H-pyran

The compound is prepared according to the procedure described inPreparation 3, except that methyl 3-bromo-methyl-benzoate is substitutedwith methyl 2-(2-bromoethyl)-benzoate and methyl magnesium iodide issubstituted with n-propyl magnesium bromide.

Preparation 19: Compound 14(R=2-[2-[4-tetrahydro-4H-pyran-2-yl)-oxy-4-heptyl]-phenyl)-ethyl

The compound is prepared according to the procedure described inPreparation 4, except that2-[2-(3-bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran issubstituted with2-[2-(2-bromoethyl)-phenyl)-4-heptyl-oxy]-tetrahydro-4H-pyran.

Preparation 20: Compound 15(R=2-(2-[4-tetrahydro-4H-pyran-2-yl)-oxy-4-heptyl]-phenyl)-ethyl

The compound is prepared according to the procedure described inPreparation 5, except that the compound 4 prepared in Preparation 4 issubstituted with the compound 14 prepared in Preparation 19.

Preparation 21: Methyl 2-(2-bromoethyl)-benzoate

2-(2-Bromoethyl)-benzoic acid (11.4 g, 50 mmol) is added to a solutionof diazomethan in ether at 0° C. The reaction mixture is concentrated invacuo, and the residue purified by chromatography to give the desiredcompound as a colourless oil.

Preparation 22:2-[2-(4-Bromomethyl-3-fluoro-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran

The compound is prepared according to the procedure described inPreparation 3, except that methyl 3-bromomethyl-benzoate is substitutedwith ethyl 4-bromomethyl-3-fluoro-benzoate.

Preparation 23: Compound 16(R=4-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-2-fluoro-phenylmethyl

The compound is prepared according to the procedure described inPreparation 4, except that2-[2-(3-bromomethylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran issubstituted with2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran.

Preparation 24: Compound 17(R=4-[2-(tetrahydro-4H-pyran-2-yl)-oxy-propyl-2]-2-fluoro-phenylmethyl

The compound is prepared according to the procedure described inPreparation 5, except that the compound 4 prepared in Preparation 4 issubstituted with the compound 16 prepared in Preparation 23.

Example 11(S),3(R)-Dihydroxy-20(R)-(3-(2-hydroxy-2-propyl)-phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene(Compound 101

The compound prepared in Preparation 5 (700 mg, 0.88 mmol) was dissolvedin ethyl acetate (1.0 ml). Acetonitrile (24 ml) was added under vigorousstirring. A solution of 5% hydrofluoric acid in acetonitrile/water 8:1(10.6 ml) was added, and the reaction mixture stirred under nitrogen atroom temperature for 45 minutes. Ethyl acetate (150 ml) was added, andthe reation mixture consecutively extracted with saturated aqueoussodium hydrogen carbonate (60 ml), water (3×60 ml) and saturated aqueoussodium chloride (50 ml), dried with magnesium sulphate and concentratedin vacuo. The residue was purified by chromatography (silica gel, 20%pentane in ethyl acetate as eluant) to give the title compound.

NMR: δ=0.54 (s, 3H), 1.18 (d, 3H), 1.57 (s, 6H), 1.12-2.06 (m, 15H),2.22 (bd, 1H), 2.30 (dd, 1H), 2.59 (dd, 1H), 2.82 (m, 1H), 3.45 (m, 1H),4.22 (bm, 1H), 4.35 (d, J=11.3, 1H), 4.42 (bm, 1H), 4.61 (d, J=11.3,1H), 4.99 (m, 1H), 5.32 (m, 1H), 5.99 (d, J=11.3, 1H), 6.38 (d, J=11.3,1H), 7.20 (bd, 1H), 7.30 (t, 1H), 7.40 (bd, 1H), 7.50 (bd, 1H), ppm.

Example 21(S),3(R)-Dihydroxy-20(R)-(4-(2-hydroxy-2-propyl)-phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene(Compound 102)

This compound was prepared by following the procedure of Example 1 andsubstituting the compound prepared in Preparation 8 for the compoundprepared in Preparation 5.

NMR: δ=0.54 (s, 3H), 1.16 (d, 3H), 1.58 (s, 6H), 1.10-2.10 (m, 15H),2.17 (m, 1H), 2.32 (dd, 1H), 2.60 (m, 1H), 2.83 (m, 1H), 3.43 (m, 1H),4.23 (m, 1H), 4.35 (d, J=11.3, 1H), 4.43 (m, 1H), 4.57 (d, J=11.3, 1H),5.00 (m, 1H), 5.32 (m, 1H), 6.00 (d, J=11.2, 1H), 6.39 (d, J=11.2, 1H),7.32 (d, 2H), 7.45 (d, 2H) ppm.

Example 31(S),3(R)-Dihydroxy-20(R)-(3-(3-hydroxy-3-pentyl)-phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene(Compound 103)

This compound was prepared by following the procedure of Example 1 andsubstituting the compound 9 prepared in Preparation 11 for the compound5 prepared in Preparation 5.

NMR: δ=0.54 (s, 3H), 0.74 (t, 6H), 1.17 (d, 3H), 1.10-2.10 (m, 19H),2,19 (bd, 1H), 2.31 (dd, 1H), 2.59 (dd, 1H), 2.81 (bd, 1H), 3.45 (m,1H), 4.22 (m, 1H), 4.33 (d, 1H), 4.42 (m, 1H), 4.62 (d, 1H), 5.00 (m,1H), 5.32 (m, 1H), 5.99 (d, 1H), 6.38 (d, 1H), 7.18 (m, 1H), 7.27 (m,2H), 7.38 (bs, 1H) ppm.

Example 41(S),3(R)-Dihydroxy-20(R)-(2-(2-hydroxy-2-methyl-propyl)-phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),-10(19)-triene(Compound 104)

This compound is prepared by following the procedure of Example 1 andsubstituting the compound 11 prepared in Preparation 14 for the compound5 prepared in Preparation 5.

Example 51(S),3(R)-Dihydroxy-20(R)-(3-(2-hydroxy-propyl-2)-6-methyl-phenylmethyloxy)-9,10-seco-pregna-5(Z),7(E),-10(19)-triene(Compound 105)

This compound is prepared by following the procedure of Example 1 andsubstituting the compound 13 prepared in Preparation 17 for the compound5 prepared in Preparation 5.

Example 61(S),3(R)-Dihydroxy-20(R)-(2-(2-(4-hydroxy-4-heptyl)-phenyl)-ethyloxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene(Compound 106)

This compound is prepared by following the procedure of Example 1 andsubstituting the compound 15 prepared in Preparation 20 for the compound5 prepared in Preparation 5.

Example 71(S),3(R)-Dihydroxy-20(R)-(4-(2-hydroxy-propyl-2)-2-fluoro-phenylmethyloxy-9,10-seco-pregna-5(Z),-7(E),10(19)-triene(Compound 107)

This compound is prepared by following the procedure of Example 1 andsubstituting the compound 17 prepared in Preparation 24 for the compound5 prepared in Preparation 5.

Example 8 Capsules Containing Compound 101

101 is dissolved in arachis oil to a final concentration of 1 μg 101/mloil. 10 Parts by weight of gelatine, 5 parts by weight glycerine, 0.08parts by weight potassium sorbate, and 14 parts by weight distilledwater are mixed together with heating and formed into soft gelatinecapsules. These are then filled each with 100 μl of the 101 in oilsolution, such that each capsule contains 0.1 μg 101.

Example 9 Dermatological Cream Containing Compound 101

In 1 g almond oil is dissolved 0.05 mg 101. To this solution is added 40g of mineral oil and 20 g of self-emulsifying beeswax. The mixture isheated to liquify. After the addition of 40 ml hot water, the mixture ismixed well. The resulting cream contains approximately 0.5 μg of 101 pergram of cream.

What we claim is:
 1. A compound of the formula I ##STR7## in which R¹and R² may be the same or different and stand for hydrogen, C₁ -C₅-alkyl, C₃ -C₇ -cycloalkyl, or taken together form a C₃ -C₈ carbocyclicring; X stands for hydrogen or hydroxy, R³ and R⁴, which may be the sameor different stand for hydrogen, C₁ -C₅ -alkyl or halogen, n is 0, 1 or2 and m is 0, 1 or 2; and derivatives of the compounds of formula I inwhich one or more hydroxy groups have been transformed into --O--acyl or--O--glycosyl or phosphate ester groups, such ester groups beinghydrolyzable in vivo.
 2. A diastereoisomer of a compound according toclaim 1 in pure form or in a mixture of diastereoisomers.
 3. A compoundaccording to claim 1, selected from the group consisting ofa)1(S),3(R)-Dihydroxy-20(R)-(3-(2-hydroxy-2-propyl)-phenylmethoxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene and b)1(S),3(R)-Dihydroxy-20(R)-(3-(3-hydroxy-3-pentyl)-phenylmethoxy)-9,10-seco-pregna-5(Z),7(E),10(19)-triene.
 4. A pharmaceutical composition containing atherapeutically effective amount of one or more of the compounds ofclaim 1, together with pharmaceutically acceptable, non-toxic carriersand/or auxiliary agents.
 5. A pharmaceutical composition according toclaim 4 in dosage unit form.
 6. A dosage unit according to claim 5containing from 0.1-50 μg of a compound of formula I.
 7. A method forproducing a compound having formula I ##STR8## in which R¹ and R² may bethe same or different and stand for hydrogen, C₁ -C₅ -alkyl, C₃ -C₇-cycloalkyl, or taken together form a C₃ -C₈ carbocyclic ring; X standsfor hydrogen or hydroxy, R³ and R⁴, which may be the same or differentstand for hydrogen, C₁ -C₅ -alkyl or halogen, n is 0, 1 or 2 and m is 0,1 or 2; and derivatives of the compounds of formula I in which one ormore hydroxy groups have been transformed into --O--acyl or--O--glycosyl or phosphate ester groups, such ester groups beinghydrolyzable in vivo comprising,a) alkylating1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-seco-pregna-5(E),7(E),10(19)-triene-20(R)-olunder basic conditions with a side chain building block of formula Z-R,in which Z is a leaving group to form a compound of formula III ##STR9##in which ##STR10## where Y is hydrogen or hydroxyl in which the hydroxylgroup may optionally be protected by a protective group and n, m, R¹,R², R³, and R⁴ are as defined above, b) photoisomerizing undertriplet-sensitized conditions a compound of the above formula III andremoving protecting groups, if present, to form the desired compound offormula I.